The objective of this project is to determine the effects of alterations in the balance of oxygen free radical metabolizing enzymes on the aging process. There is considerable interest in the role which oxygen free radicals may play in the aging process, as well as in the genesis of many types of degenerative processes and reactions to trauma. A powerful approach to the investigation of these issues is to perturb the system for handling oxygen free radicals, and many ways of doing so have been used. Genetically modified animals have been used for this purpose and have been found to be a particularly powerful method for producing the types of perturbations desired, because of both the reproducibility of the changes produced and their stability over time. In this proposal are described a series of studies of the effects of altered CuZn- superoxide dismutase (CuZnSOD) and/or MnSOD activities on age-related and induced degenerative changes in the brain, heart, and other organs, on the accumulation of mitochondrial and nuclear DNA mutations and of other biomarkers of oxidative stress, and on various aspects of mitochondrial function. Particular attention will be paid to the effects of free radical imbalance on the central nervous system, and age-dependent changes in learning and memory and in the function of the basal forebrain cholinergic system will be assessed. The animals to be studied will include transgenic mice overexpressing either CuZnSOD or MnSOD, mutant mice completely lacking in CuZnSOD, and mice with absent or very low levels of MnSOD. To engineer the mice with low levels of MnSOD activity, the tetracycline-regulated transgenic transactivator system will be used and will be adapted to produce low expression of the gene for MnSOD. The strains of genetically altered mice which will be generated in this project, along with those which already exist, constitute a unique set of model animals which will make it possible to study the effects on age-related degenerative processes of intracellular SOD activities ranging from absent to greatly elevated and of the resulting alterations of superoxide levels.